The development of new drugs, formulations and other systems for administration of physiologically active peptides and proteins, and other hydrophobic drugs or therapeutics is driven by the need to achieve the desirable physiological effects. Peptides and proteins have been observed to be unstable in blood and the gastro-intestinal tract and therefore may need to be stabilized or protected prior to delivery and remain protected once in either the gastro-intestinal tract or the circulation. Once the active pharmaceutical gets into the systemic circulation, those that have low molecular masses tend to have short biological half-lives due to their efficient removal from systemic circulation via kidneys. Furthermore, a fraction of them can also be removed via reticuloendothelial uptake due to recognition by monocyte/macrophages or as a result of opsonization by complement components. They can also lose their activity in vivo due to proteases and other enzymes.
Existing drug delivery systems can, in part, circumvent these undesirable effects and can be useful for peptide and protein delivery in vivo, with certain shortcomings, as noted. First, a continuous systemic infusion of drug via a pump can be employed. This strategy is proven efficient in clinical practice but may be impractical for outpatients requiring high levels of mobility, associated disadvantages of quality of life and potential intravenous (I.V.) line infections.
Second, peptides and proteins can be included in an implantable pump comprised of a capsule with a membrane allowing diffusion of the drug, for example, at a desirable release rate. Due to limited volume of these capsules, peptides and proteins are often used in a concentrated formulation which leads to a loss of solubility due to aggregation and potential loss of specific activity. In most cases, the drug is usually released into the extracellular space and distributed in lymphatics. Overall concentration of peptide or protein may be affected by local lymph node activity and the efficacy of lymph node drainage of the implantation site. There is also a potential of host reaction to capsule material but in general, this side effect is infrequent.
Third, the drug release system can be made biodegradable as a result of encapsulation or inclusion into degradable drug delivery vehicles or carriers, e.g. polymeric matrices, particles or membrane vesicles (liposomes). These delivery systems are usually either implantable or injectable. Implantable drug delivery systems are often placed under the epidermis where the components of the system are usually slowly degraded as a result of biological activity of surrounding cells (i.e. as a result of the release of enzymes degrading chemical bonds that hold these implants together).
Polylysine and other polyamino acids have previously been modified by the attachment of phospholipid groups and used in DNA transfection (Zhou, X H et al (1991) Biochem. Biophys. Acta 1065: 8-14 and Zhou, X h, Huang L (1994) Biochem. Biophys Acta 1189: 195-203). Polylysine has also been modified by the attachment of hydrophilic groups such as polyethylene glycol, a protective group (Dash P R, et al (1997) J. Contr. Rel. 48: 269-276), and various sugars (Kollen W J W, et al, (1996) Human Gene Ther. 13: 1577-1586 and Erbacher P, et al (1997) Biochimica Biophysica Acta 1324: 27-36) but no distinct hydrophobic moiety. Additionally, various drugs (Hudecz F. et al (1993) Bioconjugate chemistry 4: 25-33) and targeting residues such as transferrin (Wagner, E (1994) Adv. Drug Delivery Rev. 14: 113-135), asialoglycoprotein (Chowdhury, N R et al (1993) J. Biol. Chem. 268: 11265-11271) and monoclonal antibodies (Chen, J B et al (1994) Febs Lett 338: 167-169) have been conjugated to polylysine.
U.S. Pat. No. 5,871,710 to Bogdanov et al. discloses a biocompatible graft co-polymer adduct including a polymeric carrier, a protective chain linked to the polymeric carrier, a reporter group linked to the carrier or to the carrier and protective chain, and a reversibly linked Pt(II) compound for diagnosis.
U.S. Pat. No. 7,138,105 to Bolotin discloses a biocompatible graft co-polymer comprising of a metal bridge flanked by two metal binding molecules wherein one of the metal binding molecules is part of, or covalently linked to, the therapeutic agent. The bridge links the carrier and therapeutic agent capable of binding
U.S. Pat. No. 6,576,254 to Uchegbu discloses polyamino acid vesicles comprising of polylysine grafted with MPEG, fatty acids and cholesterol.